You are currently viewing our boards as a guest which gives you limited access to view most discussions and access our other features.
Come join us in on one of the best online fitness communities. We have 16,000 members that are likeminded towards a fitness, bodybuilding lifestyle. Registration is free and only takes but a few minutes. By joining our free community you will have access to communicate privately with other members (PM), respond to polls, upload content and access many other special features. You will be able to create threads to discuss and or create a fitness regimen. Or just bounce ideas off of some very knowledgeable members. So don't miss out.
Registration is fast, simple and absolutely free so please, join our community today!

Clomiphene is a SERM. It binds to the estrogen receptors and acts as both an agonist and antagonist. This means that it can both activate the estrogen receptors and also block or prevent the receptor from activating, because of this it has both estrogenic and anti-estrogenic effects. I will try to give a simplified explanation of why clomid can have contradictory effects and why understanding this is important. First let me briefly review what most of you may already know about how clomid and other SERMS work to increase natural testosterone production, as well as increase fertility by promoting spermatogenesis, while at the same time preventing gynecomastia. As we know, one of the drawbacks of exogenous testosterone is that it can cause infertility as well as lead to gyno. Taking an AI may help prevent gyno, but does nothing to promote spermatogenesis or improve testicular function.

Although only FDA approved for treating ovulation disorders in women, clomid has been successfully used for many years off-label to restore testicular function, increase fertility, as well as treat gynecomastia. It is very important to emphasize that all of these beneficial effects of clomid use in men result from its anti-estrogenic effects, not its pro-estrogenic effects. In fact the pro-estrogenic effects of clomid have the exact opposite effects, just the opposite of what we want to achieve. The net effects of clomid tend to be positive only because the anti-estrogenic effects dominate the pro-estrogenic effects. What if it were possible to achieve the beneficial anti-estrogenic effects without any of the adverse pro-estrogenic effects?

Clomid promotes testicular function by blocking estrogen receptors in the hypothalamus region of the brain. This blocks the negative feedback loop of the HPT axis increasing LH and FSH which in turn stimulate the testes to produce both sperm and testosterone. Testosterone plays a crucial role in spermatogenesis, but unfortunately exogenous testosterone only increases systemic test levels, not intratesticular levels which need to be much higher than systemic levels for spermatogenesis to occur. Similarly, clomid prevents gyno by blocking estrogen receptors in breast tissue; but it doesn’t do this as well as other SERMS such as tamoxifen. Without getting into all of the details about different types of estrogen receptors (alpha and beta) etc. a major problem with clomid is that the positive benefits of its antagonistic effects are completely offset by agonistic effects in the very same tissue types. If we had a version of clomid that had purely antagonistic effects, it should in theory do everything we want much better. In fact, just such a form of clomid exists and is available for us to use. It is called enclomiphene.

How is it possible for a single compound to have opposite effects in the very same tissue type? Actually, clomiphene is a mixture of two different versions, which are called “isomers”. They have the same chemical formula, but slightly different molecular structures. The antagonistic isomer is called “enclomiphene” and the agonistic one is called “zuclomiphene”. Zuclomiphene binds to and activates the estrogen receptors having opposite effects of enclomiphene. It is anti-gonadotropic lowering LH and FSH and it promotes breast tissue proliferation rather than inhibit it. Fortunately, regular clomid is composed of 70% enclomiphen and only 30% zuclomiphene, which explains why in most tissue types clomid is more anti-estrogenic than it is pro-estrogenic.

Enclomiphen has been very thoroughly studied for many years for use in males to treat hypogonadism. It has been shown to be safe and to be effective at restoring testosterone and sperm levels in men who had previously taken exogenous testosterone.(ref) It appears to have the benefits of test without the adverse effects; but unfortunately it still hasn’t been FDA approved. The FDA has been quibbling about technical details of the experimental design in phase III clinical trials. Theoretically, it should work better than regular clomid for PCT, and might even be good to use on cycle to maintain function and fertility while also preventing gyno. I would be very interested to hear from anyone here who has used enclomiphene whether or not it worked any better than regular clomid.

An important benefit of using enclomiphene instead of regular clomid is that doing so completely eliminates the many adverse side effects of clomid including effects on mood and vision, mucus production, etc. These effects appear to be caused by the zuclomiphene component of clomid. Remember zuclomiphene strongly activates estrogen receptors throughout the body including tissues in the brain, eyes, breasts, gut, heart etc. producing a very wide range of (mostly adverse) physiological effects. Enclomiphene, on the other hand, has none of these effects; it merely blocks estrogen receptors, which is precisely what hypogonadal males want in order to restore both sperm and testosterone production.

Another problem with clomid is that it cannot be used long-term. Why not? Because there is a huge difference in the half-life of the two component isomers. The anti-estrogenic enclomiphene has a very short half-life of only 10hrs, meaning that after one day a single dose is nearly completely gone. Zuclomiphene has a much longer half-life of 30 days! Initially clomid is antiestrogenic because it is 70% enclomiphene, but over time the pro-estrogenic zuclomiphene component builds up to dangerously high levels producing all of the unwanted sides. Evidence seems to indicate that pure enclomiphene could be safely taken for long periods of time in order to restore and maintain fertility, testicular function (and to prevent gyno) while avoiding most of the adverse effects of clomid. In the event some adverse effect is experienced, immediate cessation should solve the problem. With clomid adverse effects can continue for a very long time. Please remember enclomiphene has not been FDA approved for use in humans. More research is needed to establish safety and efficacy, optimal dosing, etc. My comments are based solely on theory. I have no personal experience with any of these compounds. However, in the near future I may start conducting my own studies, using lab rats, of course.

This is interesting to me and makes me feel like I need to brush off some cobwebs. I completely understand the negative feedback loop between T & E2, and have probably taught it to more people than I can count. I understand the theory of what your are stating above, however, I goes make me wonder about a couple of things. Most notably, we do need some estrogen so the agonist function of Clomid can serve a purpose.

When we discontinue a cycle and go into PCT our T levels will drop, no shocker to anyone here. However, if T is low then so is E. The negative feedback loops, and we have tons of them, are the body's way of creating homeostasis. While tricking the pituitary with the antagonist effect of Clomid is important it would seem that we still need some circulating E. The agonist function of Clomid comes in and acts or mimics E in a sense. I have never studied the different isomers of Clomid, however, it seems like enclomiphene, only serving as the antagonist, may leave an imbalance if used alone. Then again, I do realize that Clomid was developed and studied for use in women and what women need we might not.

I would be interested in more research on this topic even though I'm on TRT and won't be doing PCT. Also, has anyone used it and have experiences they can report. Is it available or even obtainable?

This is interesting to me and makes me feel like I need to brush off some cobwebs. I completely understand the negative feedback loop between T & E2, and have probably taught it to more people than I can count. I understand the theory of what your are stating above, however, I goes make me wonder about a couple of things. Most notably, we do need some estrogen so the agonist function of Clomid can serve a purpose.

When we discontinue a cycle and go into PCT our T levels will drop, no shocker to anyone here. However, if T is low then so is E. The negative feedback loops, and we have tons of them, are the body's way of creating homeostasis. While tricking the pituitary with the antagonist effect of Clomid is important it would seem that we still need some circulating E. The agonist function of Clomid comes in and acts or mimics E in a sense. I have never studied the different isomers of Clomid, however, it seems like enclomiphene, only serving as the antagonist, may leave an imbalance if used alone. Then again, I do realize that Clomid was developed and studied for use in women and what women need we might not.

I would be interested in more research on this topic even though I'm on TRT and won't be doing PCT. Also, has anyone used it and have experiences they can report. Is it available or even obtainable?

Hey Rip, how you doing my brother? Haven't seen you my friend in ages. Shoot me a PM so we can catch up.
In answer to your question, remember enclomiphene does not prevent the aromatization of test, so if you're on TRT, you'll have plenty of estrogen. Not sure what dose you consider TRT, but most TRT docs prescribe 200 to 250 mg of test//week which is 2 to 3 times what the body naturally produces so you will actually have excessive levels of estrogen. So, in your case you do not need the agonistic effects of regular clomid. The antagonistic effects of enclomiphene will block some of your estrogen receptors which is a good thing, it should also theoretically reduce the negative feedback loop preserving natural testosterone production, testicular function, spermatogenesis (which requires natural production, not exogenous supplementation) and fertility. Of course, you're right that some estrogen is important for health and too much e receptor antagonism could have adverse effects. So the question is what is the optimal dose to maintain testicular function without blocking all estrogenic activity. I have no way to answer this question. It is going to vary tremendously from individual to individual. But I believe enclomiphene is a safer alternative to potent AI's like letro which can potentially completely block estrogen production. No matter how high a dose of en-clomid you take, it is never going to completely block all e-receptors, so you're always going to have some estrogenic activity. Remember my comments are quite speculative, based on my (limited) understanding of the underlying physiological processes, without any actual experience with enclomiphene. This is why I welcome feedback from those who may have used en-clomid. It appears to be available from many research chem suppliers, but of course I can not vouch for the quality of what they offer.
For those who are not transitioning to TRT, but want to do PCT in order to restore their natural production of test (and also estrogen) as quickly as possible would there be any possible advantage to using regular clomid over en-clomid? In my opinion, no absolutely not. Remember the agonistic zuclomiphene component of regular clomid is antigonadotropic, lowering LH and FSH, so this would only delay recovery. I can think of no reason why a healthy male would ever prefer regular clomid to en-clomid, whether on cycle, off-cycle, on TRT or during PCT. Doing so would only be counter productive. I recommend an AI on cycle and if needed on TRT, but not during PCT, because as you correctly point out some estrogen is important. I have suggested that using en-clomid long-term either on cycle or during TRT could reduce or eliminate the need for an AI; but how well such an approach would work would require more data and individual experimentation, depending on different individual rates of aromatization, etc. During PCT in addition to clomid (or preferably en-clomid) I also recommend taking tamoxifen. Although both are classified as SERMs they work thru somewhat different mechanisms and have additive effects, so taking both together will have a synergistic effect on restoring natural production and has been shown to shorten recovery times. I hope this answers your questions. Just my opinion, if you have different reasoning, i'd like to hear it.